Alzheimer's disease (AD), a major cause of morbidity and mortality, is caused at least in part by the toxicity of Abeta, a proteolytic product of a receptor-like protein called amyolid-beta precursor protein (APP). Although much progress was made in the understanding of how APP cleavage generates Abeta, the normal functions of APP, the relation of these functions to Abeta production and AD pathogenesis, and the mechanism by which Abeta damages neurons are incompletely understood. Recent studies suggest that AD is initially a disease of synapses, and that the characteristic cognitive impairment of early AD is due to a loss of synapse function. AD may affect synapses because synapses are exquisitely sensitive to injury, and/or because the function of APP acts directly or indirectly on synapses. The overall goal of the current application is to follow up on this hypothesis by utilizing the tools and reagents that our laboratory has developed to analyse synapse function. We aim to characterize the possible physiological role of APP at the synapse, and to examine how the synaptic etiology of AD is related to this physiological role. Since diverse functions have been associated with APP and a variety of mechanisms have been invoked in the pathogenesis of AD, this application proposes a wide spectrum of approaches ranging from cell biology and biochemical protein purification to genetic experiments in mice. These experiments will investigate the functions of APP, and relate these functions to the production and pathogenicity of Abeta. Specifically, we propose to identify and functionally characterize extracellular ligands for APP as a first approach to understanding the function of the conserved extracellular sequences of APP (specific aim 1), a goal that was already partially achieved in preliminary results with the isolation of specific APP ligands. We also propose to test the possible role of APP as a transcriptional regulator (specific aim 2), a role that we recently identified in transactivation experiments, and to analyze the functions of Mints, which bind to APP (specific aim 3). Furthermore, we propose to examine the relation of APP cleavage and Abeta production to intracellular membrane traffic and its regulation, and to test the physiological significance of APP cleavage (specific aim 4). Finally, we propose to clarify the question whether Abeta exerts a specifically synaptic toxicity, and to investigate the mechanism of its toxicity by using novel mouse models of AD that allow a more mechanistic approach than currently available models (specific aim 5). Together these studies will contribute to our understanding of APP function and Abeta toxicity in AD, and may suggest new avenues for interfering with the pathogenesis of AD.